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A new class of mechanism-based inhibitors for Trypanosoma cruzi trans-sialidase and their influence on parasite virulence.
- Source :
-
Glycobiology [Glycobiology] 2010 Aug; Vol. 20 (8), pp. 1034-45. Date of Electronic Publication: 2010 Apr 22. - Publication Year :
- 2010
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Abstract
- One of the most interesting aspects of Trypanosoma cruzi is its adaptation to obtain sialic acid from its host, fulfilling this need exclusively through the reaction catalyzed by enzymatically active trans-sialidase (aTS), thought to play an important role in the pathogenesis of Chagas' disease. Herein, we report that 2-difluoromethyl-4-nitrophenyl-3,5-dideoxy-d-glycero-alpha-d-galacto-2-nonulopyranosid acid (NeuNAcFNP) inactivates aTS time- and dose-dependently, and this inhibition was not relieved removing the inhibitor. Also, NeuNAcFNP causes a decrease in infection of mammalian cells. Characterization of labeled aTS by matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry revealed that inactivation of the enzyme occurs through formation of a covalent bond between Arg245 and Asp247 and the inhibitor aglycone. Participation of Asp247 in the catalytic mechanism was proved by constructing a TSD247A mutant, which presents only residual activity. Molecular dynamic simulations indicate that the D247A mutation results in a more open catalytic cleft. In summary, NeuNAcFNP is the first reported mechanism-based inhibitor of aTS, representing a new template for drug design and opening new possibilities for chemotherapy of Chagas' disease, as well as for the elucidation of aTS function in T. cruzi pathogenesis and biology.
- Subjects :
- Animals
Biocatalysis drug effects
Dose-Response Relationship, Drug
Enzyme Inhibitors chemistry
Glycoproteins chemistry
Glycoproteins metabolism
Molecular Dynamics Simulation
Molecular Structure
Neuraminidase chemistry
Neuraminidase metabolism
Sialic Acids chemistry
Structure-Activity Relationship
Trypanosoma cruzi drug effects
Enzyme Inhibitors pharmacology
Glycoproteins antagonists & inhibitors
Host-Parasite Interactions drug effects
Neuraminidase antagonists & inhibitors
Sialic Acids pharmacology
Trypanosoma cruzi enzymology
Trypanosoma cruzi pathogenicity
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2423
- Volume :
- 20
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Glycobiology
- Publication Type :
- Academic Journal
- Accession number :
- 20466651
- Full Text :
- https://doi.org/10.1093/glycob/cwq065